Over 200 million major elective surgeries are performed worldwide per year. With the rising costs of healthcare, preventative measures grow increasingly relevant to medical practice. Preconditioning (PC), a preemptive therapy in which mildly harmful stimuli are administered to induce endogenous protective mechanisms prior to major injury, has shown to be protective in many injury models. Given the elective nature of most neurosurgical procedures, the surgical brain injury (SBI) model is an ideal platform for PC. In SBI, collateral damage to healthy tissue caused by neurosurgical maneuvers-incision, retraction, and electrocoagulation-result in brain edema and hemorrhage. We propose PC with small doses of Crotalus snake venom, known for their inflammatory and hemorrhagic effects, to increase tolerance to SBI. Crotalus venoms contain two proteins of interest to SBI PC: phospholipase 2 (PLA2), an enzyme upstream to COX-2 in the inflammatory cascade, and snake venom metalloproteinase (sMMP), an enzyme with hemorrhagic effects. Crotalus venoms have been studied for diagnostic capabilities as well as therapeutic effects in coagulative disorders; and will soon be a new avenue of therapy for SBI by utilizing their toxic properties to preemptively upregulate the endogenous response to inflammatory and hemorrhagic injury. Our central hypothesis is that PC with Crotalus venom (CV-PC) will temper the severity of SBI by inducing innate tolerance to injury. This premise is supported by our preliminary data, which demonstrate that CV-PC reduces brain edema and hemorrhage, and improves neurological function 24 hrs after SBI in rats. We propose to systematically examine the effects of and investigate the molecular mechanisms for CV-PC. In our first aim, we will evaluate brain edema and hemorrhage for CV-PC, and determine optimal dosing and toxicity of CV-PC. We expect that CV-PC will reduce the brain edema, hemorrhage, and neurological deficits that result from SBI. In our second aim, we will examine the expression of inflammatory mediators after SBI, evaluate the effects of antagonizing PLA2 and COX-2 while administering CV-PC, and administer PLA2 as a preconditioning treatment in SBI. We expect that CV-PC produces neuroprotective effects for SBI through the PLA2/COX-2 inflammatory signaling pathway. In our third aim, we will measure plasma fibrinogen and fibrinogen degradation products, determine coagulative parameters, and evaluate the effects of antagonizing sMMP in CV-PC. We expect CV- PC reduces hemorrhage in SBI via its fibrinogenolytic activity. Our long-term goal is to develop an effective, preemptive therapy for SBI. Our proposal aims to establish a better mechanistic understanding of SBI that will facilitate the application of preconditioning therapies in the clinic. If successful, this proposal will improve patient outcome and decrease costs of perioperative care for neurosurgical patients and could prove beneficial in other major elective surgeries as well.